A Mutation in Rab38 Small GTPase Causes Abnormal Lung Surfactant Homeostasis and Aberrant Alveolar Structure in Mice
A Mutation in Rab38 Small GTPase Causes Abnormal Lung Surfactant Homeostasis and Aberrant Alveolar Structure in Mice
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DOI：
10.2353/ajpath.2008.080056
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发表时间：
2008-11-01
影响因子：
6
通讯作者：
Voelker, Dennis R.
中科院分区：
文献类型：
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作者：
Osanai, Kazuhiro;Oikawa, Rieko;Voelker, Dennis R.
巧克力突变，这是与眼皮肤白化病的小鼠，已被归因于G146 T颠换的保守GTP/GDP相互作用域的Rab 38，一个小的GT3调节细胞内囊泡运输。Rab 38显示出独特的组织特异性表达模式，在肺中表达水平最高。本研究的目的是表征Rab 38-G146 T对肺表型的影响，并研究突变基因产物（Rab 38（cht）蛋白）的分子基础。巧克力肺表现出均匀扩大的远端空气空间与轻度肺泡破坏，以及轻微增加肺顺应性。肺泡型H细胞充血，板层体的大小和数量增加。肺组织中的疏水性表面活性剂成分（即磷脂酰胆碱和表面活性剂蛋白B）增加，但肺泡腔中减少，这与板层体分泌功能障碍和这些细胞器的后续细胞蓄积一致。与野生型Rab 38相比，天然Rab 38（cht）蛋白被发现是亲水性的并且不与细胞内膜结合。出乎意料的是，重组Rab 38（CHT）蛋白保留了GTP结合活性，但未能进行异戊二烯基修饰，这是膜结合活性所需的。这些结果表明，Rab 38的遗传异常影响多种溶酶体相关的细胞器，导致肺部疾病，除了眼皮肤白化病。(Am J Pathol 2008，173：1265-1274; DOI. 10.2353/ajpath.2008.080056）
The chocolate mutation, which is associated with oculocutaneous albinism in mice, has been attributed to a G146T transversion in the conserved GTP/GDP-interacting domain of Rab38, a small GTPase that regulates intracellular vesicular trafficking. Rab38 displays a unique tissue-specific expression pattern with highest levels present in the lung. The purpose of this study was to characterize the effects of Rab38-G146T on lung phenotype and to investigate the molecular basis of the mutant gene product (Rab38(cht) protein). Chocolate lungs exhibited a uniform enlargement of the distal airspaces with mild alveolar destruction as well as a slight increase in lung compliance. Alveolar type H cells were engorged with lamellar bodies of increased size and number. Hydrophobic surfactant constituents (ie, phosphatidylcholine and surfactant protein B) were increased in lung tissues but decreased in alveolar spaces, consistent with a malfunction in lamellar body secretion and the subsequent cellular accumulation of these organelles. In contrast to wild-type Rab38, native Rab38(cht) proteins were found to he hydrophilic and not bound to intracellular membranes. Unexpectedly, recombinant Rab38(cht) proteins retained GTP-binding activity but failed to undergo prenyl modification that is required for membrane-binding activity. These results suggest that the genetic abnormality of Rab38 affects multiple lysosome-related organelles, resulting in lung disease in addition to oculocutaneous albinism. (Am J Pathol 2008, 173:1265-1274; DOI. 10.2353/ajpath.2008.080056)